Use of acetoacetylamino diphenyl amines as antiinflammatory agents

ABSTRACT

N-AROMATIC SUBSTITUTED ACID AMIDE COMPOUNDS OF THE FORMULA   (R4,R5-PHENYL)-Y-C&lt;(=C(-R3)-CH=C(-NH-CO-CH(-R2)-Z-CH3)-   C=X-)   WHEREIN: THE ACYL IS THE ACYL GROUP OF A LOWER ALIPHATIC, PREFFERABLY, ALKYL CARBOXYLIC ACID OR OF A MONOALIPHATIC, PREFERABLY, ALKYL ESTER OF CARBONIC ACID, R2 IS H OR LOWER ALKYL, R3 IS H, HALOGEN ALKYL OR LOWER ALKOXY, EACH OF R4 AND R5 TAKEN INDIVIDUALLY IS HYDROGEN, HALOGEN, LOWER ALKYL, NITRO, TRIFLUOROMETHYL, LOWER ALKOXY, LOWER ALKYL AMINO, AMINO, HYDROXY, ACYL-OXY AS DEFINED ABOVE OR ACYL-AMINO AS DEFINED ABOVE, X IS=N-OR=CH-AND Y IS-CH2-OR-NHAND WHEREIN WHEN Z IS   Z IS -CO-, -CH(-OH)- OR -CH(-O-ACYL)-   X IS CH AND Y IS NH AT LEAST ONE OF R2, R3, R4 AND R5 IS OTHER THAN HYDROGEN. SUCH COMPOUNDS HAVE VALUABLE PHARMACEUTICAL PROPERITIES, SUCH AS, ANTIINFLAMMATORY, ANALGESIC, ANTIPYRETIC AND/OR ANTISPASMODIC PROPERTIES.

United States Patent M 3,719,762 USE OF ACETOACETYLAMINO DIPHENYL ANHNESAS ANTIINFLAMMATORY AGENTS Kurt Thiele, Frankfurt, Germany, assignor toDeutschc Goldunil Silber-Scheideanstalt vormals Roessler, Frankfurt amMain, Germany No Drawing. Continuation-impart of applications Ser. No.682,616, Nov. 13, 1967, and Ser. No. 840,816, July 10, 1969. Thisapplication Aug. 25, 1970, Ser. No. 66.883 Claims priority, applicationGermany, Nov. 16, 1966, D 51,561; Sept. 1, 1967, D 53,982 Int. Cl. A61k27/00 US. Cl. 424-324 15 Claims ABSTRACT OF THE DISCLOSURE N-aromaticsubstituted acid amide compounds of the wherein:

Z is C, CH- or CH O H -acy1 wherein X is CH and Y is NH at least one ofR R R and R is other than hydrogen. Such compounds have valuablepharmaceutical properties, such as, antiinfiammatory, analgesic,antipyretic and/ or antispasmodic properties.

The present application is a continuation-in-part of application Ser.No. 682,616, filed Nov. 13, 1967, now Pat. No. 3,474,107, Oct. 21, 1969,and application Ser. No. 840,816, filed July 10, 1969, and now Pat. No.3,567,765.

The compounds useful in the invention have been described above and canbe prepared by conventional methods, for instance, by reacting acompound of the formula with an acid of the formula CE3-ZCHC O OK3,719,762 Patented Mar. 6, 1973 or its corresponding halide, ester,amide, anhydride or ketene.

The present application is particularly concerned with thepharmaceutical use of compounds having the formula wherein R is hydrogenor lower alkyl, R, is hydrogen, halogen, lower alkyl or lower alkoxy,each of R and R is hydrogen, halogen, lower alkyl, nitro,tri-fiuoromethyl, lower alkoxy, lower alkylamino, amino, hydroxy, loweracyloxy and lower acylamino and Y is CH;, or NH with the proviso thatwhen Y is NH at least one of R R R, and R is other than hydrogen.

The compounds according to the invention when they contain basic centerscan be converted to their pharmaceutically acceptable acid additionsalts. Also, in the event they are racemates they can be resolved intothe optically active isomeric components. Optically active startingmaterials also can be employed right from the start.

The compounds according to the invention, as already indicated, possessvaluable pharmaceutical properties, among which are analgesic,antipyretic, antispasmodic and especially antiinfiammatory propertiesalthough in some instances compounds may exhibit some of such propertiesto a greater extent than the others and in some instances, for instance,some of such properties may be lacking.

The dosages in general, for example, can be between about 1 and 300mg./kg. oral. The compounds are well tolerated, for example, their acutetoxicity with mice expressed as LD in mg./kg. is between 700 and 4000rug/kg.

The compounds according to the invention can, for example, be dividedinto the following groups based on chemical constitution and activity.

(A) Diphenyl methane and pyridyl phenyl methane derivatives (compoundsof Formula I wherein Y=CH This group of compounds has an especially goodantiinfiammatory action and a weaker analgesic action.

Antiinflarnmatory Compound 0! action in Analgesic Example No. percentaction 5 67 Present. 6 66 Do.

(B) Aceto acetyl amino-diphenyl amine derivatives (compounds of FormulaI wherein Y=NH, X=CH and These compounds also have antiinfiammatoryaction but no analgesic action).

Antlinflarnmatory Compound of action in Analgesic Example No. percentaction 4 46 None. 8 31 Do.

addition a good analgesic action and in some instances antipyretic andantispasmodic action).

Compound of Example No 3 Antiinflammatory action in percent 94 Analgesicaction ED in mg./kg. oral 71-85 Antipyretic action ED in rug/kg. 17Antispasmodic action in percent with dosage 32 Antiinflammatory actionin percent Compound of Example No.

Analgesic aetivi ty Present. None.

D0. Present.

Do. None.

Do. Do.

(E) Hydroxy butryamino phenylamino pyridine derivatives (compounds ofFormula I wherein Y=NH,

: =N, and

Z=-CH or CH-O-acyl The activity of these compounds is similar to that ofthe compounds of group A and of Group D). Analgesic activity has onlybeen found present in one of such compounds and in this instance it isvery strong.

Antiinflammatory action in Analgesic percent action Compound of ExampleNo.

82 None.

51 Very strong. 43 None.

The antiinflammatory action was ascertained by the method according toDomenjoz et al., Arch. exp. Pharm. Path. 230, 325, 1957, at a 300mg./kg. oral dosage and the antiinflarnmatory action expressed inpercent of reduction of edema in ovalbumen edema of the rat paw asagainst untreated controls. The antiinflammatory action is of the sametype as the action of the known antiinfiammatory agent phenyl butazone.

The analgesic action was ascertained by the mouse tail test according toHafiner, Deutsche Med. Wochenschrift 55, 731, 1929, with oral dosages of1 to 500 mg./kg.

The anti-pyretic action was ascertained by yeast fever in rats (0.Biich, Arch. intern. Pharmacodyn, 123, 140, 1959).

The antispasmodic action was ascertained by tests on whole animals(rats) by measurement of the reduction in intestinal motility bymeasurement of the degree to which the passage of the test meal throughthe small intestine was slackened.

The application of the compounds according to the invention can be oral,perlingual, parenteral or in the form of an aerosol.

The following examples will serve to illustrate the novel compoundsaccording to the invention.

EXAMPLE 1 2-phenylamino-5-aceto acetyl amino-pyridine (a) 6.8 g. (0.081mol) of diketene were added portionwise at 20 C. to a solution of 15 g.(0.081 mol) of 2-phenyl-amino-5-amino-pyridine in ml. of dioxane. Afterthe addition was completed, the mixture was stirred for a further 30minutes. The crystallized product which already started to precipitateout during the addition of the diketene was filtered oil andrecrystallized from isopropanol petroleum ether. The melting point was153- 154 C. and the yield 11 g.

(b) A suspension of 18.5 g. (0.1 mol) of 2-anilino-5- amino-pyridine in100 ml. of xylene, to which 3 drops of pyridine had been added, wasadded in the course of 1 /2 to 2 hours at 135-140 C. to a mixture of15.6 g. (0. 12 mol) of freshly distilled aceto acetic ester, 100 ml. ofp-xylene and 3 drops of pyridine' in a 500 ml. 4- necked flask providedwith a stirrer, dropping funnel, descending fractionating column andthermometer. About the same quantity of liquid should be distilled offat the descending condenser as is delivered from the suspension. Themixture was then heated under reflux for a further 2 hours. The productcrystallized out upon cooling. Petroleum ether was added and thecrystals filtered oil and recrystallized twice fromisopropanol/petroleum ether. Its melting point was 152153 C. and theyield 12.5 g.

EXAMPLE 2 2-phenylamino-5- (3 -hydroxy-butyramino) -pyridine 20 g.(0.0745 mol) of Z-phenylarnino-S-aceto acetyl amino-pyridine weredissolved in a mixture of ml. of dioxane and 400 ml. of methanol. Then2.8 g. of sodium borohydride was added portionwise to such solution atabout 5-10 C. while stirring. After completion of the addition thecooling bath was removed so that the temperature of the mixture raisedto room temperature. Thereafter it was heated a short time to 50 C. andthe solution concentrated under vacuum. Water was added to the solidresidue and the mixture thoroughly triturated, filtered, washed severaltimes with water, dried and recrystallized from isopropanol/ petroleumether. The product was obtained in a yield of 16 g. with a melting pointof 161-162 C.

EXAMPLE 3 4- 3-hydroxy-butyramido -diphenyl amine 2.1 g. (0.0555 mol) ofsodium borohydride were added portionwise to a solution of 15 g. (0.0555mol) of 4-aceto acetyl amino-diphenyl amine in 100 ml. of methanolcooled to 10 C. After the reaction had ended the mixture was heated to50 C. for about 15 minutes. The solution was concentrated and wateradded to the residue and the mixture thoroughly triturated, filtered,washed several times with water, dried and recrystallized from alcohol/petroleum ether. The product was obtained in a yield of 11.5 g. with amelting point of 127-128 C.

EXAMPLE 4 3-methoxy-4-aceto acetyl amino-diphenyl amine CHaO 15 g. (0.07mol) of 3-methoxy-4-amino-diphenyl amine were suspended in 100 ml. ofether and 5.9 g. (0.07 mol) of diketene added thereto while stirring.The reaction occurred very soon in that a clear solution resulted withwarming from which the reaction product soon crystallized out. Thereaction mixture was stirrred for a further hour and the product thenfiltered off and recrystallized from isopropanol. Its melting point was124125 C. and the yield was 16 g.

EXAMPLE 4-aceto acetyl amino-diphenyl methane ona-oo-oni-oo Nn--orn@10.5 g. (0.123 mol) of diketene were added to a solution of 22.5 g.(0.123 mol) of 4-amino-diphenyl methane in 70 ml. of dioxane. During theensuing reaction the temperature rose up to 60 C. After the solution hadcooled down again 300 ml. of water were added. The oily product whichseparated out became solid upon trituration. It was stirred up well withwater, filtered off, washed several times with water, dried andrecrystallized from a mixture of gasoline (B.P. 100-140 C.) andisopropanol. The product was obtained in a yield of 21.5 g. with amelting point of 88-89 C.

EXAMPLE 6 4-(3-hydroxy-butyramido) -diphenyl methane out-i H-oH. oO-NH-Q-Clir-Q 20 g. (0.075 mol) of the product of Example 5 weredissolved in 200 ml. of methanol and 2.9 g. (0.077 mol) of sodiumborohydride added to the solution while stirring at 5-10" C. After thereaction ended the reaction mixture was heated for 30 minutes at 50 C.After concentrating the solution and stirring up the syrupy residue withwater a crystalline substance was obtained. This was stirred up againwith water, filtered off, washed with water and recrystallized fromalcohol/water. The product was obtained in a yield of 17.2 g. with amelting point of 110- 111 C.

EXAMPLE 7 2-phenyl amino-S- 3-oxo-2-butyl-butyramino -pyridine Asolution of 1.2 g. of sodium (0.057 mol) in 50 ml. of alcohol was addedto a solution of 14 g. (0.057 mol) of 2-phenyl-5-aceto-acetylamino-pyridine. The mixture was heated under reflux for 2 hours andthereafter 8.2 g. (0.06 mol) of butyl bromide added thereto. Thereaction mixture then was again heated under reflux for 8 hours,concentrated, the residue stirred up with water and filtered off. Theproduct after recrystallization from alcohol/ water had a melting pointof 146-147 C. The yield was 7 g.

EXAMPLE 8 4- 3-oxo-2-butyl-butyramino) -diphenylamine CHa-C o-Em-oO-NH-Q-NH-Q 6 EXAMPLE 9 2-(4-methyl-anilino)-5-aceto acetylamino-pyridine NH- CH: N G

EXAMPLE 10 CHs-CO-CHz-C O-NH 2-(2-rnethoxy anilino)-5-aceto acetylamino-pyridine (SCH:

17 g. (0.079 mol) of 2-(2-methoxy anilino)-5-aminopyridine weredissolved in ml. of benzene and 8 g. of diketene (content of diketeneabout 84%) added portionwise thereto while stirring at 20-25 C. Afterthe addition was completed the mixture Was heated to 50 C. for 30minutes. After the reaction mixture had cooled down to room temperature,gasoline was added until the solution just began to cloud. The compoundsoon crystallized out and was filtered 011? and washed with ether. Itwas then dissolved in 100 ml. of hot isopropanol and filtered hot. Afterit had cooled somewhat 100* ml. of gasoline were added. The solution wasstored in a refrigerator and the product which crystallized out filteredoff, washed with 50 ml. of 1:1 isopropanol/gasoline and dried. The yieldwas 13.4 g. or about 57% of theory. Its melting point was 81-82 C.

The following compounds were prepared analogously: d (a) 2-(2-ethoxyanilino)-5-aceto acetyl amino-pyri- CHa-CO-GHzCONH 002K:

The yield was 51% of theory and its melting point was 1 17-1 18 C. d (b)2-(4-ethoxy anilino)-5-aceto acetyl amino-pyri- CHaC O-CHz-G O-NH I Theyield was 68% of theory and after recrystallization from methanol itsmelting point was 152-153 C.

(c) 2-(3-trifiuoromethylamino)-5-aceto acetyl amino- The yield was 51%of theory. After recrystallization from isopropanol its melting pointwas 127-128 C.

7 EXAMPLE 11 4-(d,l-B-acetoxy-butyramino)-diphenyl amine -o O-CHa Asolution of 18.8 g. (0.12 mol) of d,lfl-acetoxy butyric acid chloride in50 ml. of benzene was gradually added while stirring to a solution of21.1 g. (0.115 mol) of p-aminodiphenylamine in 100 ml. of benzene and16.5 ml. of triethylamine at about C. After the addition was completedthe reaction mixture was stirred for a further minutes at C. Aftercooling, water and ether were added and the mixture thoroughly shaken.The organic phase was separated ofi, dried and concentrated. The syrupyresidue solidified upon standing and was twice recrystallized fromisopropanol/petroleum ether. The yield of the product was 19 g. or about53% of theory and its melting point was 138-139" C.

EXAMPLE 12 4- (d,l-fi-hydroxy-butyramino -diphenyl amine 0.5 g. of 85%powdered caustic soda (0.76 mol) was dissolved in 50 ml. of 10% alcohol.After the addition of 2 g. of the product of Example 11 the reactionmixture was heated under weak refluxing conditions for about 2 hours.The solution was then evaporated to dryness and the residue trituratedwith Water, filtered and dried. The product was recrystallized twicefrom isopropanol/ petroleum ether. The yield was 0.75 g. or about 43% oftheory and its melting point was 126-127 C.

EXAMPLE 13 2-(2,5-dimethoxy anilino)-5-aceto acetyl aminopyridine 25 g.(0.102 mol) of 2-(2,5-dimethoxy anilino)-5- amino pyridine weredissolved in 150 ml. of acetone. Then 10 g. of 84% diketene (0.102 mol)were added gradually while stirring. After the addition was complete themixture was stirred for a further hour at 50 C. The solution wasconcentrated and the residue mixed with water and the mixture shaken outwith ethyl acetate. The organic phase was separated off, dried withpotash, filtered and concentrated. The residue was dissolved in hotisopropanol. Upon cooling a dark viscous oil first separated out fromthe solution. The clear solution was poured off therefrom. The productrecrystallized out from the solution and the crystallization wascompleted by allowing the mixture to stand overnight in a refrigerator.The crystallized product was filtered off and dissolved in 70 ml. ofalcohol. The solution was heated hot with charcoal and filtered. Afteraddition of 50 ml. of gasoline the product crystallized out again. Itwas filtered off, washed with ether and dried. The melting point thereofwas 103104 C. and the yield 10.5 g.

EXAMPLE l4 2- (2-eth0xy anilino -5- (fi-hydroxy-butyramino) -pyridine 30g. (0.096 mol) of 2-(2-ethoxy anilino)-5-aceto acetyl amino-pyridinewere dissolved in 200 ml. of methanol. 3.64 g. (0.096 mol) of powderedsodium borohydride were added portionwise to the solution while stirringand while cooling the solution to maintain a temperature between 1+5 C.and +10 C. After the addition was completed the cooling bath was removedand after about 2 hours standing the solution was concentrated and wateradded to the syrupy residue and the mixture allowed to stand for severalhours. When no crystallization occurred even after such standing, thewater was decanted off as much as possible and the residue dissolved inalcohol, the alcohol solution dried with potash, filtered andconcentrated. 28 g. of the product were obtained. The maleic acid saltwas prepared therefrom in alcoholic solution. Such salt wasrecrystallized from alcohol/ether. The yield was 30 g. or about 72.5% oftheory. Its melting point was EXAMPLE l5 2- (4-ethoxy anilino) -5-(B-hydroxy-butyramino pyridine 31.3 g. (0.1 mol) of 2-(4-ethoxyanilino)-5-aceto acetyl amino-pyridine were dissolved in 400 ml. ofmethanol. 3.8 g. (0.1 mol) of sodium borohydride were added portionwisewhile stirring at room temperature. After the addition was completed themixture was stirred for a further hour. The mixture was thenconcentrated and the crystallized residue placed on a filter and washedwith water and with isopropanol. The crude product was recrystallizedfrom isopropanol. The melting point of the product was 151152 C. and theyield 16 g. or about 51% of theory.

EXAMPLE 16 2-(3-trifiuoromethyl anilino)-5- (B-hydroxybutyramino-pyridine 16.5 g. (0.05 mol) of 2-(3-trifluoromethyl anilino)-5- acetoacetyl amino-pyridine were dissolved in ml. of methanol. 2.1 g. (0.055mol) of powdered sodium borohydride were added portionwise whilestirring at room temperature and the mixture stirred thereafter for 1hour. The solution was concentrated and water added to the crystallineresidue and the mixture filtered. The resulting product wasrecrystallized from isopropanol with addition of water. The meltingpoint of the product was 14l-142 C. and the yield 10.5 g. or 66% oftheory.

EXAMPLE 17 2- (4-ethyl anilino -5- (B-hydroxy butyramino pyridine 15 g.(0.055 mol) of 2-(4-ethyl anilino)-5-aceto acetyl amino-pyridine weredissolved in a mixture of 50 ml. of dioxane and 100 ml. of methanol. 2g. (0.052 mol) of powdered sodium borohydride were added portionwisewhile stirring at 10 C. and thereafter the mixture stirred for a further2 hours at room temperature. The solution was concentrated and wateradded to the syrupy residue. Upon crystallization the mixture wasthoroughly stirred and the crystals filtered oif, washed with water anddried. 15 g. of the dry substance were dissolved in isopropanol and thesolution filtered. 200 ml. of gasoline were added to the filteredsolution and the mixture stored over night in a refrigerator. Thecrystals which separated out were filtered off, washed with ether anddried. The melting point of the product was 1181l9 C. and the yield 11g.

EXAMPLE l8 Analogously to Example 9',4-methyl-4-acetoacetylaminodiphenylamine was obtained from 4-methy1-4'-aminodiphenylamine and diketene. Upon recrystallization from isopropanolthe compound had a melting point of -l16 C.

EXAMPLE 19 Analogously to Example 9,4-methoxy-4'-acetoacetylamino-diphenylamine was obtained from4-methoxy-4'- aminodiphenylamine and diketene. Upon recrystallizationfrom isopropanol the compound had a melting point of 128-130 C.

EXAMPLE 20 Analogously to Example 2,4-methyl-4'-(3-hydroxybutyryl)-amino-diphenylamine was obtained from 4-methyl-4-acetoacetylamino-diphenylamine by reduction with sodiumborohydride. Upon recrystallization from isopropanol the compound had amelting point of 144- 145 C.

EXAMPLE 21 Analogously to Example 20,4-methoxy-4'-(3-hydroxybutyryl)-aminodiphenylamine was obtained from 4-methoxy-4'-acetoacetylamino-diphenylamine by reduction with sodiumborohydride. Upon recrystallization from isopropanol the compound had amelting point of 132- 133 C.

EXAMPLE 22 4- fi-hydroxy-butyramino -4 amino-diphenyl-aminoCHa-EH-(JHz-CO-NH-Q-NH-QNIE This compound is produced by catalyticreduction of 4 (6 hydroxy butyramino) 4'-nitro-diphenyl-amino. Yield:approximately 86 percent of the theoretical value; RR: 144 to 145 C.

EXAMPLE 23 4-acetoacetyl-amino-4-nitro-diphenyl-amino 24 gm. (0.105mole) of 4-amino-4'-nitro-diphenylamine are suspended in 200 ml. ofdioxane. After adding approximately 0.5 ml. of triethyl amine and 10.5(0.105 mole) of diketene the reaction temperature increases to 40 C.within 20 minutes and a clear solution forms. The solution is heated for2 hours to 60 C. It is then mixed with water and a dark oil is separatedwhich becomes solid after some time. The product is filtered withsuction, washed with Water and after boiling with methanol it isrecrystallized from isopropanol. Yield: 8.3 gm., RR: 192 to 193 C.

EXAMPLE 24 4-(fl-hydroxy-butyramino)-4'-nitro-diphenyl-amine Thecompound is produced from 4-acetoacetyl-amine- 4-nitro-diphenyl-amine byreduction with sodium borate in the usual manner. The yield isapproximately 60 percent of the theoretical value. The melting point is165 to 167 C.

In addition to the compounds set forth supra, there also are included,for example, the following compounds within the invention 4-3-oxo-2-methyl-butyramino -diphenyl amine; 3 3-oxo-2-ethyl-butyraminophenyl 2,5 'dimethylphenyl amine; 3-butoxy-4-(3-hydroxybutyramido)diphenyl amine, 2-chloro-4-acetoacetyl aminodiphenyl amine,3-bromo-4-acetoacetyl amino diphenyl amine;3-trifluoromethyl-4-acetoacetyl aminodiphenyl amine; 4-[2fluoro-(3-hydroxybutyramido) ]-diphenyl amine;2-methyl-4-acetoacetylaminodiphenyl amine;2-methyl-4-acetoacetylamino-3'-butyl diphenylamine having the formulaCH3 Cam;

2-butyl-4-acetoacetylamino-3'-methyl 4-butyl diphenyl methane;

3-propoxy-4-acetoacetylamino-diphenyl amine;

4-acetoacetylamino-4'-chlorodiphenyl amine,

4-(3-hydroxybutyramido)-4-bromodiphenyl methane;

4- 3-hydroxybutyramido -4'-trifluoromethyl diphenyl amine;

4-acetoacetylamino-2',4'-dichlorodiphenyl amine;

10 4-acetoacetylamino-2,3'-di(trifiuoromethyl) diphenyl methane;4-acetoacetylamino-2-methyl-4-butoxy diphenyl amine; 4-3-hydroxybutyramido -3 '-aminodiphenyl amine; 4- 3-hydroxybutyramido-4-methylamino diphenyl methane; 4-acetoacetylamino-2'-butylaminodiphenyl amine; 4-acetoacetylamino- 4-hydroxy diphenyl amine; 4- 3-hydroxybutyramido) -2',4-dihydroxy diphenyl amine; 4-(fl-butyroxy-butyramino -diphenyl amine; 4-( fi-valeroxy-butyramino-diphenyl methane; 4-(fi-carbonatoethylbutyramino -diphenyl amine; 4-B-carbonatomethyl-butyramino -diphenyl methane having the formula4-acetoacetylamino 3'-nitro diphenylamine; 4-acetoacetylamino-3'-nitro4'-hydroxy diphenyl amine; 4-acetoacetylamino- 4-acetoxydiphenyl amine;4-acetoacetylamino-4-butyramino diphenyl amine.

The term lower alkyl as is understood in the art has 1 to 6 carbonatoms.

In the work reported below using compounds from the examples where Z isthe conditions employed were as follows. The antiphlogistic(antiinflammatory) action was tested partially on albumen edema,partially on carrageenin edema of the rat paw using the procedure ofDomenjoz et al., Arch. exp. Pharm. Path. 230, 325, (1957) (albumenedema) and the procedure of Winter et al. J. 'Pharmacol. exp. Therap.141, 319, (1963) (carrageenin edema) The testing for acute toxicity onmice was carried out orally according to the method of Miller andTainter, Proc. Sec. Exp. Biol. Med. 57, 261, (1944) with an observationtime of 24 hours. For each substance about animals were tested.

The analgesic action was ascertained by the mouse tail test according toHaffner, Deutsche Med. Wochenschrift 55, 731, (1929).

The results are given in the following table:

Table antiphlogistic action (edema reduction) E D5 =dosage at which 50%of the mice tested did not react to the pain irrltant.

2 LDs rats orally.

As can be seen from the table in regard to carrageenin edema thecompound of Example 18 is about as strongly effective in antiphlogisticactivity as phenylbutazone but it is about 415 times less toxic to rats.This means that the compound of Example 18 at equal efiectivenespossesses a 4 to 5 times better tolerance than phenylbutazone.

The compound of Example 5 is about half as effective as phenylbutazonebut it is, however, nearly 3 times less toxic so that in regard toantiphlogistic action and toxicity the antiphlogistic action of thecompound of Example 5 clearly is superior to phenylbutazone. Analogous11 results can be seen with the other compounds in the table.

The claimed compounds are useful as therapeutics in the followingillnesses.

Chronic polyarthritis Illnesses of the rheumatic groups Post traumaticinflammation Swellings in fractures Thrombophlebitis in any form (alsopost operative) Bursitis Synovitis Collagenoses (polymyositis)pericarteriitis Gout The compounds can be administered enterally, forexample in the form of tablets, capsules, pills, drages, suppositories,oils and aqueous solutions, suspensions and emulsions. Also they can beadministered parenterally, for example as injectable aqueous or oilysolutions or suspensions.

In oral administration to animals the claimed com pounds have goodantiphlogistic activity for example in the range of 10-1000 mg./kg. Whenemployed, for example intravenously they are efiective at 1-100 mg./kg.e.g. 10 mg./kg. They can be used with mammals such as dogs, cats,cattle, humans.

Based on animal tests the entrapolated dosage of the claimed compoundspermitted with humans for oral application is between about 25 and 5000mg./per human/ per day.

In parenteral administration, for example, intramusculiarly the dosageis about 5-1000 rug/per human/per The acute toxicity of the claimedcompounds in mice is between 100 and over 4000 mg./kg. orally and as setforth previously with the specific compounds disclosed is over 700mg./kg.

EXAMPLES OF PHARMACEUTICAL PREPARATIONS With the use of the customarypharmaceutical assistants the active materials of the invention areprocessed by known methods to the desired form of administration such astablets, capsules, drages, suppositories, suspensions, salves, orsolution, for oral, parenteral or local application and the like.

Since the compounds are relatively difficulty soluble in water these areemployed in a given case to obtain the necessary concentration of activematerial organic solvents or agents alone or in admixture with eachother or with water. As physiologically compatible organic solvents oragents there can be used among others mono and polyhedric alcohols, e.g.ethyl alcohol, propyl alcohol, ethylene glycol, propylene glycol,glycerine, sorbitol and polyglycols, e.g. diethylene glycol,polyethylene glycol 400, dipropylene glycol, triethylene glycol andtheir derivatives, e.g. ethylene glycol monomethyl ether, ethyleneglycol monoethyl ether, diethylene glycol monoethyl ether and diethyleneglycol monomethyl ether, dimethyl sulfoxide, etc.

There are added if necessary to the medicinal preparations preservativessuch as sorbic acid, p-hydroxybenzoic acid esters and the like.

On the assumption that no chemical and physiological incompatibilityexists there can be added to the medicinal preparations containing thematerials of the invention other active materials such as, for example,spasm dissolving, pain alleviating agents, etc.

The following examples illustrate several typical compositions andprocesses for their preparation and do not describe all of the forms ofpreparation:

Example A 10.0 grams of the compound of Example 4 were dissolved in 1000ml. of polyethylene glycol 400 with slight 12' heating. The solution wasmade up to 2000 ml. with water for injection, passed through asterilization filter and filled into 2 ml. glass ampoules in knownmanner. The production of the injection solution can take place understerile precautions. Likewise it is possible to work under normalconditions and subject the filled ampoules to a heat sterilization.

1 ampoule of 2 ml. capacity contains 10 mg. of 3-methoxy-4-acetoacetylamino-diphenylamine and serves as a single dose.

Example B 20 grams of the compound of Example 5 were dissolved withslight heating in 1000 ml. of polyethylene glycol 400. In the samemanner as in Example A these were produced in 2 ml. ampoules containing10 mg. of 4-acetoacetylamino-diphenyl methane.

Example C 1.0 grams of 4-(3-oxo-2-butyl-butyramino)-diphenyl amine(prepared in Example 8) was dissolved in a mixture of 600 ml. of1,2-propylene glycol and 100 ml. of ethanol with slight heating and thesolution made up to 1000 ml. with water. Ampoules containing 1 ml. ofthis solution were made up as in Example 1.

Example D 50.0 grams of the compound of Example 18 were worked into 1950grams of melted suppository base (for example hard fat DAB 7 which is amixed glyceride) and in known manner poured in the form of 2.0 gramssuppositories. Each suppository contained 50 mg. of 4-acetoacetylamino-4'-methyl-diphenyl amine.

Example E 10.0 grams of the compound of Example 19 were granulated inknown manner with 10.0 grams of microcrystalline cellulose and 124.5grams of lactose with about 50 ml. of a 10% starch glue. The drygranulate which passed through an about 1 mm. mesh width sieve was mixedwith 40.0 grams of cornstarch, 20.0 grams of talc, 10.0 grams ofmicrocrystalline cellulose and 0.5 gram of highly dispersed silica geland pressed in :known manner to tablets having a weight of 220 mg. and adiameter of 9 mm.

1 tablet contained 10 mg. of 4-acetoacetylamino-4'- methoxydiphenylamine.

Example F 10 grams of the compound of Example 19 were dissolved in ml.of dimethyl sulfoxide and made up to ml. with water. The 10% activematerial solution served for local application, e.g. to the skin.

Example G 500.0 grams of the compond of Example 4 were granulated withabout 25 0 ml. of ethanol (96% weight/ volume) after drying passedthrough a sieve having a mesh width of 0.5 mm. and filled intoindividual dosage of 250 mg. in gelatin stick capsules, size 00. As asingle dosage these can be taken orally 1-2 capsules, corresponding to250500 mg. of active material.

What is claimed is:

1. A method of producing an antiinflammatory eifect in a mammal selectedfrom the group consisting of humans, dogs, cats and cattle comprisingadministering to said mammal a suificient dosage to produce such effectof a compound having the formula where R is hydrogen or alkyl of 1-6carbon atoms, R is hydrogen, methyl, methoxy, propoxy, chloro, bromo 14or trifluoromethyl, R and R are hydrogen, hydroxy, 12. The method ofclaim 1 wherein the compound is alkyl of 1 to 6 carbon atoms, methoxy,butoxy, acetoxy, 4-acetoacetyl-amino-4-nitro-diphenyl amine. nitro,chloro or trifiuoromethyl, Y is CH or NH and 13. The method of claim 1wherein the dosage is bewhen Y is NH at least one of R R R and R isother tween 5 and 5000 mg. per day of the compound. than hydrogen. 5 14.The method of claim 13 wherein the administra- 2. The method of claim 1wherein R is hydrogen. tion is orally and the dosage is between 25 and5000 3. The method of claim 2 wherein the dosage is bemg. per day of thecompound. tween 5 and 5000 mg. per day of active material and 15. Themethod of claim 13 wherein the administration the mammal is human. isparenterally and the dosage is between 5 and 1000 4. The method of claim2 where Y is -NH-. 10 mg. per day of the compound.

5. The method of claim 2 where Y is -CH 6. The method of claim 1 whereinthe References Cited CH -C-OH-OONH UNITED STATES PATENTS 2 15 3,474,10710/1969 Thiele 260-2955 group is in the 4' position Th ele 7. The methodof claim 1 wherein the compound is 3,377,315 4/1968 Ashton et a1 X3-methoXy-4-aceto acetyl amlno-diphenyl amine. OTHER REFERENCES 8. Themethod of claim 1 wherein the compound is 4-aceto acetyl amino-diphenylmethane.

9. The method of claim 1 wherein the compound is4-(3-oxo-2-butyl-butyramino)-diphenyl amine. ALBERT MEYERS, PrimaryEXamlIlel 10. The method of claim 1 wherein the compound is LSCH-ENKMAN, Assistant Examiner 4-methy1-4'-aceto-acetylamino-diphenylamine.

11. The method of claim 1 wherein the compound is 25 US, Cl, X R4-methoxy-4'-aceto-acetylamino-diphenyl amine. 424-263 ChemicalAbstracts 32: 4797 4798 (1938).

